Repeated exposure to drugs of abuse produces specific neuroadaptations in the mesolimbic dopamine system that could alter both the primary and secondary reinforcing properties of the drugs, and contribute to relapse of drug-seeking behavior. In the nucleus accumbens (NAc), some of these neuroadaptations could result from altered gene expression mediated by drug-induced changes in the transcription factors, CREB (cAMP-Response Element Binding protein) and deltaFosB, a Fos-related Antigen (FRA) induced by chronic, but not acute, drug exposure. Similarly, repeated drug exposure produce an up-regulation of GluR1, an AMPA glutamate receptor subunit, in the ventral tegmental area (VTA), and a down-regulation of the GluR2 subunit in the NAc. Our hypothesis is that these neuroadaptations contribute to specific motivational changes associated with drug addiction, for example with sensitization or tolerance to the reinforcing properties of the drugs, or to enhance the ability of drugs, stress, and drug-associated (conditioned) stimuli to trigger relapse of drug-seeking behavior. The proposed studies will test the hypothesis by using animals with genetically altered levels of these target proteins in the VTA and NAc 1) by direct transfection with a viral vector containing the gene for the target protein in rats; and 2) by using mutant mice that lack or over express the gene for the target protein. Preliminary studies demonstrate that these genetically modified animals exhibit altered responses to drugs of abuse in other drug-related behaviors (see Behavioral Core). The studies in Project 4 will extend these studies by testing the effects of genetically modulating the target protein on direct behavioral measures of the primary and secondary reinforcing properties of drugs, and relapse of drug-seeking behavior triggered by drugs, conditioned stimuli, and stress. Some neuroadaptations to chronic drug exposure resemble a neurodegenerative process, and can be prevented or reversed by infusion or neurotrophic factors into the VTA or NAc. Moreover, some of the neuroadaptations mentioned above can be modified by these factors. Preliminary studies have found highly potent actions of neurotrophic factors on drug-related behaviors. Since these various neuroadaptations are hypothesized to contribute to motivations changes associated with drug addiction, the proposed studies will test whether treatment with neurotrophic factors can alter direct behavioral measures of primary and secondary drug reinforcement, and relapse of drug-seeking behavior triggered by drugs, conditioned stimuli, and stress.